248281-84-7

Usage

Uses

Used in Pharmaceutical Industry:
CIVENTICHEM CV-4057 is used as an immunomodulator for the treatment of multiple sclerosis. It has demonstrated efficacy in reducing inflammation and autoimmunity, which are key factors in the progression of the disease.
CIVENTICHEM CV-4057 is also used as a potential treatment for Huntington's disease. It has shown positive results in disease models, suggesting its potential to alleviate symptoms and improve the quality of life for patients.
Additionally, due to its immunomodulatory properties, CIVENTICHEM CV-4057 may have applications in other areas of medicine where inflammation and autoimmunity play a significant role, such as autoimmune disorders and certain types of cancer. Further research and clinical trials would be necessary to explore these potential applications fully.

in vitro

abr-215062 was shown to completely inhibit the development of murine acute experimental autoimmune encephalomyelitis (eae) [1].

in vivo

abr-215062 dose-dependently inhibited disease and showed better disease inhibitory effects as compared to roquinimex (linomide). furthermore, abr-215062 inhibited the inflammation of both cd4+ t cells and macrophages into central nervous tissues [2].

References

J?nsson et al. (2004), Synthesis and Biological Evaluation of New 1,2-Dihydro-4-hydroxy-2-oxo-3-quinolinecarboxamides for Treatment of Autoimmune Disorders: Structure-Activity Relationship; Med. Chem. 47 2075 Rothhammer et al. (2021); Aryl Hydrocarbon Receptor Activation in Astrocytes by Laquinimod Ameliorates Autoimmune Inflammation in the CNS, Neurol. Neuroimmunol. Neuroinflamm., 8 e946 Pitarokoili et al. (2014), Laquinimod exerts strong clinical and immunomodulatory effects in Lewis rat experimental autoimmune neuritis; Neuroimmunol., 274 38 Ott et al. (2019), Laquinimod, a prototypic quinoline-3-carboxamide and aryl hydrocarbon receptor agonist, utilizes CD155-mediated natural killer/dendritic cell interaction to suppress CNS autoimmunity; Neuroinflammation, 16 49 Kaye et al. (2016), Laquinimod arrests experimental autoimmune encephalitis by activating the aryl hydrocarbon receptor; Natl. Acad. Sci. USA., 113 E6145 Th?ne and Linker (2016), Laquinimod in the treatment of multiple sclerosis: a review of the data so far; Drug Des. Devel. Ther., 10 1111 Dobson et al. (2016), Laquinimod dampens hyperactive cytokine production in Huntington’s disease patient myeloid cells; Neurochem., 137 782 Garcia-Miralles et al. (2016), Laquinimod rescues striatal, cortical and white matter pathology and results in modest behavioural improvements in the YAC128 model of Huntington disease; Rep., 6 31652

InChI:InChI=1/C19H17ClN2O3/c1-3-22(12-8-5-4-6-9-12)19(25)16-17(23)15-13(20)10-7-11-14(15)21(2)18(16)24/h4-11,23H,3H2,1-2H3

Synthetic route

1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxylic acid methyl ester (637027-41-9) + N-ethyl-N-phenylamine (103-69-5) → laquinimod (248281-84-7)

Conditions	Yield
In n-heptane for 6.58333h; Heating;	98%
In n-heptane	98%
In n-heptane for 4h; Product distribution / selectivity; Reflux; Molecular sieve;	98%
In n-heptane for 6h; Reflux;	97%
In octane; n-heptane at 112℃; for 5h; Inert atmosphere; Large scale;	96%

1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxylic acid methyl ester (637027-41-9) + N-ethyl-N-phenylamine (103-69-5) → 5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxoquinoline + laquinimod (248281-84-7)

Conditions	Yield
In n-heptane Heating / reflux;	A n/a B 98%
In toluene Heating / reflux;	A n/a B 98%
In n-heptane for 6.58333h; Heating / reflux;	A 0.03% B 98%
In toluene for 3.25h; Heating / reflux;	A 0.54% B 90%

1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxylic acid methyl ester (637027-41-9) + N-ethyl-N-phenylamine (103-69-5) → methanol (67-56-1) + laquinimod (248281-84-7)

Conditions	Yield
In n-heptane for 6.58333h; Product distribution / selectivity; Heating / reflux;	A n/a B 98%

5-chloro-N-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-N-phenyl-3-quinolinecarboxamide sodium salt → laquinimod (248281-84-7)

Conditions	Yield
With hydrogenchloride In water	96%
Stage #1: 5-chloro-N-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-N-phenyl-3-quinolinecarboxamide sodium salt With sodium hydroxide In water at 50℃; pH=12.5; Stage #2: With hydrogenchloride In ethanol; water at 4℃; pH=5; Product distribution / selectivity;	56.2%

N-ethyl-N-phenylamine (103-69-5) + 5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxylic acid (335640-50-1) → laquinimod (248281-84-7)

Conditions	Yield
With thionyl chloride; triethylamine In dichloromethane at 0 - 20℃; for 4.5h;	87%
With dicyclohexyl-carbodiimide In toluene at 80℃; for 4h; Reagent/catalyst; Inert atmosphere; Large scale;	62%
Stage #1: N-ethyl-N-phenylamine With dichlorotriphenylphosphorane In chloroform at 25 - 30℃; for 0.25h; Inert atmosphere; Stage #2: 5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxylic acid In chloroform at 25 - 45℃; Product distribution / selectivity;

methyl 2-chloro-6-[[3-(ethyl(phenyl)amino)-3-oxopropanoyl]methylamino]benzoate (1379595-99-9) → laquinimod (248281-84-7)

Conditions	Yield
Stage #1: methyl 2-chloro-6-[[3-(ethyl(phenyl)amino)-3-oxopropanoyl]methylamino]benzoate With sodium methylate In tetrahydrofuran; methanol for 2h; Inert atmosphere; Reflux; Stage #2: With water; sodium hydroxide In methanol at 5℃; for 0.5h; Stage #3: With hydrogenchloride In methanol; water Product distribution / selectivity;	87%

5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxylic acid ethyl ester (248282-10-2) → laquinimod (248281-84-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 0.1 h / 100 °C / microwave irradiation 2: 98 percent / heptane / 6.58 h / Heating View Scheme
Multi-step reaction with 2 steps 1: 91 percent / HCl / acetic acid / 6 h / 60 °C 2: 87 percent / SOCl2; Et3N / CH2Cl2 / 4.5 h / 0 - 20 °C View Scheme

5-chloro-1H-benzo[d][1,3]oxazine-2,4-dione (20829-96-3) → laquinimod (248281-84-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: NaH / dimethylformamide / 5 h / 20 °C 2: NaH / dimethylformamide / 5 h / 85 °C 3: 91 percent / HCl / acetic acid / 6 h / 60 °C 4: 87 percent / SOCl2; Et3N / CH2Cl2 / 4.5 h / 0 - 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: sodium carbonate / N,N-dimethyl-formamide / 1.25 h / 0 - 30 °C / Inert atmosphere 2.1: sodium methylate / N,N-dimethyl-formamide / 1.5 h / 25 - 85 °C / Inert atmosphere 2.2: 1.17 h / 80 - 85 °C 2.3: 2 h / 25 - 30 °C / pH 1 3.1: hydrogenchloride; acetic acid / 80 - 85 °C 4.1: dichlorotriphenylphosphorane / dichloromethane / 0.25 h / 25 - 30 °C / Inert atmosphere 4.2: 3 h / 25 - 45 °C View Scheme
Multi-step reaction with 2 steps 1.1: sodium hydride / mineral oil; N,N-dimethyl acetamide / 45 °C / Inert atmosphere 1.2: 2 h / 20 °C / Inert atmosphere 2.1: sodium hydride / mineral oil; N,N-dimethyl acetamide / 7 h / 85 °C / Inert atmosphere View Scheme

2-chloro-6-aminobenzoic acid (2148-56-3) → laquinimod (248281-84-7)

Conditions	Yield
Multi-step reaction with 5 steps 1: dioxane / 1 h / 20 °C 2: NaH / dimethylformamide / 5 h / 20 °C 3: NaH / dimethylformamide / 5 h / 85 °C 4: 91 percent / HCl / acetic acid / 6 h / 60 °C 5: 87 percent / SOCl2; Et3N / CH2Cl2 / 4.5 h / 0 - 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: 1,4-dioxane / 12 - 20 °C 2.1: sodium hydride / mineral oil; N,N-dimethyl acetamide / 45 °C / Inert atmosphere 2.2: 2 h / 20 °C / Inert atmosphere 3.1: sodium hydride / mineral oil; N,N-dimethyl acetamide / 7 h / 85 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: 1,4-dioxane / 12 - 20 °C 2: potassium carbonate / N,N-dimethyl-formamide / 72 h / 20 °C / Inert atmosphere; Large scale 3: sodium hydride / mineral oil; N,N-dimethyl acetamide / 7 h / 85 °C / Inert atmosphere View Scheme

5-chloro-N-methylisatoic anhydride (40707-01-5) → laquinimod (248281-84-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: NaH / dimethylformamide / 5 h / 85 °C 2: 91 percent / HCl / acetic acid / 6 h / 60 °C 3: 87 percent / SOCl2; Et3N / CH2Cl2 / 4.5 h / 0 - 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: sodium methylate / N,N-dimethyl-formamide / 1.5 h / 25 - 85 °C / Inert atmosphere 1.2: 1.17 h / 80 - 85 °C 1.3: 2 h / 25 - 30 °C / pH 1 2.1: hydrogenchloride; acetic acid / 80 - 85 °C 3.1: dichlorotriphenylphosphorane / dichloromethane / 0.25 h / 25 - 30 °C / Inert atmosphere 3.2: 3 h / 25 - 45 °C View Scheme
Multi-step reaction with 2 steps 1: mineral oil; N,N-dimethyl acetamide / 5 h / 85 °C / Inert atmosphere 2: n-heptane; octane / 5 h / 112 °C / Inert atmosphere; Large scale View Scheme
Multi-step reaction with 3 steps 1: mineral oil; N,N-dimethyl acetamide / 5 h / 85 °C / Inert atmosphere 2: hydrogenchloride; acetic acid; water / acetic anhydride / 2 h / 20 - 85 °C / Inert atmosphere; Large scale 3: dicyclohexyl-carbodiimide / toluene / 4 h / 80 °C / Inert atmosphere; Large scale View Scheme
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 20 °C / Inert atmosphere 1.2: 5 h / 80 °C 2.1: n-heptane / 6 h / Reflux View Scheme

N-ethyl-N-phenylamine (103-69-5) + 5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxylic acid ethyl ester (248282-10-2) → laquinimod (248281-84-7)

Conditions	Yield
In n-heptane

1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxylic acid methyl ester (637027-41-9) → laquinimod (248281-84-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydrogenchloride; acetic acid / 80 - 85 °C 2.1: dichlorotriphenylphosphorane / dichloromethane / 0.25 h / 25 - 30 °C / Inert atmosphere 2.2: 3 h / 25 - 45 °C View Scheme
Multi-step reaction with 2 steps 1: hydrogenchloride; acetic acid; water / acetic anhydride / 2 h / 20 - 85 °C / Inert atmosphere; Large scale 2: dicyclohexyl-carbodiimide / toluene / 4 h / 80 °C / Inert atmosphere; Large scale View Scheme

N-ethyl-N-phenylamine (103-69-5) → laquinimod (248281-84-7)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: dichloromethane / 14 h / 20 °C / Inert atmosphere 2.1: water; lithium hydroxide / tetrahydrofuran / 1.5 h / 20 °C 2.2: 0 - 5 °C / pH 2 - 3 3.1: pyridine / dichloromethane / 0.5 h / 20 - 25 °C / Inert atmosphere 3.2: 1 h / 0 - 5 °C 3.3: 0 - 20 °C 4.1: sodium methylate / tetrahydrofuran; methanol / 2 h / Inert atmosphere; Reflux 4.2: 0.5 h / 5 °C View Scheme
Multi-step reaction with 2 steps 1: triethylamine / acetone / 2 h / 2 - 20 °C / Inert atmosphere 2: sodium hydride / mineral oil; N,N-dimethyl acetamide / 7 h / 85 °C / Inert atmosphere View Scheme

3-(Ethyl(phenyl)amino)-3-oxopropanoic acid (118081-77-9) → laquinimod (248281-84-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: pyridine / dichloromethane / 0.5 h / 20 - 25 °C / Inert atmosphere 1.2: 1 h / 0 - 5 °C 1.3: 0 - 20 °C 2.1: sodium methylate / tetrahydrofuran; methanol / 2 h / Inert atmosphere; Reflux 2.2: 0.5 h / 5 °C View Scheme

methyl 3-(N-ethyl-N-phenylamino)-3-oxopropionate (142613-14-7) → laquinimod (248281-84-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: water; lithium hydroxide / tetrahydrofuran / 1.5 h / 20 °C 1.2: 0 - 5 °C / pH 2 - 3 2.1: pyridine / dichloromethane / 0.5 h / 20 - 25 °C / Inert atmosphere 2.2: 1 h / 0 - 5 °C 2.3: 0 - 20 °C 3.1: sodium methylate / tetrahydrofuran; methanol / 2 h / Inert atmosphere; Reflux 3.2: 0.5 h / 5 °C View Scheme

C10H10ClNO4 → laquinimod (248281-84-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: acetyl chloride / 1,4-dioxane / 10 h / 45 °C / Inert atmosphere; Large scale 2.1: sodium hydride / mineral oil; N,N-dimethyl acetamide / 45 °C / Inert atmosphere 2.2: 2 h / 20 °C / Inert atmosphere 3.1: sodium hydride / mineral oil; N,N-dimethyl acetamide / 7 h / 85 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: acetyl chloride / 1,4-dioxane / 10 h / 45 °C / Inert atmosphere; Large scale 2: potassium carbonate / N,N-dimethyl-formamide / 72 h / 20 °C / Inert atmosphere; Large scale 3: sodium hydride / mineral oil; N,N-dimethyl acetamide / 7 h / 85 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1.1: acetyl chloride / 1,4-dioxane / 10 h / 45 °C / Inert atmosphere; Large scale 2.1: sodium hydride / mineral oil; N,N-dimethyl acetamide / 45 °C / Inert atmosphere 2.2: 2 h / 20 °C / Inert atmosphere 3.1: mineral oil; N,N-dimethyl acetamide / 5 h / 85 °C / Inert atmosphere 4.1: n-heptane; octane / 5 h / 112 °C / Inert atmosphere; Large scale View Scheme

5-chloro-N-methylisatoic anhydride (40707-01-5) + methyl 3-(N-ethyl-N-phenylamino)-3-oxopropionate (142613-14-7) → laquinimod (248281-84-7)

Conditions	Yield
With sodium hydride In N,N-dimethyl acetamide; mineral oil at 85℃; for 7h; Inert atmosphere;	110 g

laquinimod (248281-84-7) → 5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxoquinoline

Conditions	Yield
In water; toluene at 140℃; for 4h;	100%
Multi-step reaction with 2 steps 1: toluene; H2O / 1 h / 100 °C 2: 98 percent / dimethylsulfoxide / 1.5 h / 70 °C View Scheme

laquinimod (248281-84-7) → N-ethyl-N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide calcium salt

Conditions	Yield
With calcium acetate In ethanol; water at 70℃; for 0.5h;	98%

laquinimod (248281-84-7) → 5-chloro-N-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-N-phenyl-3-quinolinecarboxamide sodium salt

Conditions	Yield
With sodium hydroxide In ethanol; water for 1.75h; Inert atmosphere; Large scale;	95%
With sodium methylate In methanol at 20 - 30℃;	94%
With sodium hydroxide In ethanol; water at 20℃; for 6.58333h; pH=8 - 12;	90%

laquinimod (248281-84-7) → 1H,3H-spiro[5-chloro-1-methylquinoline-2,4-dione-3,3'-[1]ethylindolin-[2]-one]

Conditions	Yield
With ammonium cerium (IV) nitrate; acetic acid In ethanol at 20℃; for 1h;	95%

L-lysine (56-87-1) + laquinimod (248281-84-7) → laquinimod L-lysine salt

Conditions	Yield
In methanol Solvent;	92.7%

aniline (62-53-3) + laquinimod (248281-84-7) → ABR-215174

Conditions	Yield
In toluene at 100℃; for 1h;	92%

laquinimod (248281-84-7) → N-ethyl-N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide iron (III) salt

Conditions	Yield
With iron(III) sulfate In chloroform; water at 40℃;	85%

cholin hydroxide (123-41-1) + laquinimod (248281-84-7) → laquinimod choline hydroxide salt (1609005-03-9)

Conditions	Yield
In methanol for 0.166667h; Solvent;	76.3%

methanol (67-56-1) + laquinimod (248281-84-7) → 1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxylic acid methyl ester (637027-41-9)

Conditions	Yield
at 100℃; for 0.1h; microwave irradiation;

methanol (67-56-1) + laquinimod (248281-84-7) → 5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxoquinoline + 1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxylic acid methyl ester (637027-41-9) + 5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxylic acid (335640-50-1)

Conditions	Yield
With water; trifluoroacetic acid In dimethyl sulfoxide; acetonitrile at 50℃; for 2h; Kinetics;

propan-1-ol (71-23-8) + laquinimod (248281-84-7) → 5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxoquinoline + 5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxylic acid n-propyl ester + 5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxylic acid (335640-50-1)

Conditions	Yield
With water; trifluoroacetic acid In dimethyl sulfoxide; acetonitrile at 50℃; for 2h; Kinetics; Further Variations:; reaction partner content;

ethanol (64-17-5) + laquinimod (248281-84-7) → 5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxoquinoline + 5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxylic acid (335640-50-1) + 5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxylic acid ethyl ester (248282-10-2)

Conditions	Yield
With water; trifluoroacetic acid In dimethyl sulfoxide; acetonitrile at 50℃; for 2h; Kinetics; Further Variations:; Reagents;

isopropyl alcohol (67-63-0) + laquinimod (248281-84-7) → 5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxoquinoline + 5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxylic acid isopropyl ester + 5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxylic acid (335640-50-1)

Conditions	Yield
With water; trifluoroacetic acid In dimethyl sulfoxide; acetonitrile at 50℃; for 2h; Kinetics;

laquinimod (248281-84-7) → 5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxoquinoline + 5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxylic acid (335640-50-1)

Conditions	Yield
In water; toluene at 100℃; for 1h;

laquinimod (248281-84-7) → 5-chloro-1,2-dihydro-4-methoxy-1-methyl-2-oxo-3-quinolinecarboxylic acid methyl ester

Conditions	Yield
Multi-step reaction with 2 steps 1: 0.1 h / 100 °C / microwave irradiation 2: 37 percent / DBU / N,N-dimethyl-acetamide / 20 h / 20 °C View Scheme

laquinimod (248281-84-7) → 5-chloro-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydroquinoline-3-carboxylic acid methyl ester

Conditions	Yield
Multi-step reaction with 2 steps 1: 0.1 h / 100 °C / microwave irradiation 2: 39 percent / DBU / N,N-dimethyl-acetamide / 20 h / 20 °C View Scheme

propan-1-ol (71-23-8) + laquinimod (248281-84-7) → 5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxylic acid n-propyl ester

Conditions	Yield
With hydrogenchloride In water at 45 - 60℃; for 4h; Reactivity;
Reflux;
With hydrogenchloride at 45 - 60℃; for 4h; Reactivity;

Upstream product

• 637027-41-9 1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxylic acid methyl ester 
• 103-69-5 N-ethyl-N-phenylamine 
• 40707-01-5 5-chloro-N-methylisatoic anhydride 
• 142613-14-7 methyl 3-(N-ethyl-N-phenylamino)-3-oxopropionate 
• 1379595-99-9 methyl 2-chloro-6-[[3-(ethyl(phenyl)amino)-3-oxopropanoyl]methylamino]benzoate 
• 118081-77-9 3-(Ethyl(phenyl)amino)-3-oxopropanoic acid 
• 248282-10-2 5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxylic acid ethyl ester 
• 2148-56-3 2-chloro-6-aminobenzoic acid 
• 20829-96-3 5-chloro-1H-benzo[d][1,3]oxazine-2,4-dione 
• 335640-50-1 5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxylic acid 

Downstream Products

• 637027-41-9 1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxylic acid methyl ester 
• 335640-50-1 5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxylic acid 
• 64460-50-0 2-methylamino-6-chlorobenzoic acid 
• 1609005-03-9 laquinimod choline hydroxide salt 
• 1609005-01-7 laquinimod meglumine salt 
• 248282-10-2 5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxylic acid ethyl ester 

Relevant academic research and scientific papers

An Efficient Method for the Synthesis of Laquinimod

Laquinimod, 5-chloro-1,2-dihydro-N-ethyl-4-hydroxy-1-methyl-2-oxo-N- phenyl-3-quinoline carboxamide, is an oral drug in clinical trials for the treatment of multiple sclerosis. An efficient synthetic method for laquinimod from 2-amino-6-chlorobenzoic acid via four steps was established. The overall yield of laquinimod is up to 82% as compared with 70% reported in literature. It has also been demonstrated that green reagent dimethyl carbonate is not suitable for the N-methylation of 5-chloroisatoic anhydride owing to the ring-cleavage reaction induced by the generated methanol. The ring-cleavage by-products were isolated and characterized by 1H-NMR and 13C-NMR. In addition, in the study of laquinimod derivatives, we found that 5-chloro-1,2-dihydro-N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-3-quinoline carboxamide (laquinimod) was obtained in much higher yield than 7-chloro-1,2-dihydro-N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-3-quinoline carboxamide under the same reaction conditions, and it is possibly attributed to a neighboring group effect.

TRANSDERMAL FORMULATIONS OF LAQUINIMOD

This invention provides a transdermal patch comprising: a) a backing layer; b) a liner; c) optionally, a highly porous membrane; and d) a pharmaceutical composition comprising: (i) optionally, a pressure sensitive adhesive in an amount of up to about 95 wt% of the pharmaceutical composition, (ii) laquinimod in an amount of about 0.1-20 wt% of the pharmaceutical composition, and (iii) optionally, one or more permeation enhancers in a total amount of up to about 70 wt% of the pharmaceutical composition. This invention also provides a method for delivering laquinimod across the skin of a subject and for treating a human subject afflicted with a form of multiple sclerosis comprising administering to the skin of the subject a transdermal patch as described herein. This invention further provides a transdermal patch as described herein for use in treating a human subject afflicted with a form of multiple sclerosis.

HIGHLY PURE LAQUINIMOD OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF

Provided herein is an impurity of laquinimod, N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxoquinoline-3-carboxamide (deschloro laquinimod impurity), and process for preparation and isolation thereof. Provided further herein is a highly pure laquinimod or a pharmaceutically acceptable salt thereof substantially free of deschloro laquinimod impurity, processes for the preparation thereof, and pharmaceutical compositions comprising highly pure laquinimod or a pharmaceutically acceptable salt thereof substantially free of deschloro laquinimod impurity.

INTERMEDIATE COMPOUNDS AND PROCESSES FOR THE PREPARATION OF QUINOLINE DERIVATIVES SUCH AS LAQUINIMOD SODIUM

The present invention relates to processes for the preparation of quinoline-3 -carboxamide derivatives, such as sodium 5-chloro-3-(ethylphenylcarbamoyl)-l-methyl-2- oxo-l,2-dihydroquinolin-4-olate (Laquinimod sodium). The present invention further relates to intermediates formed in such processes.

1,2-DIHYDRO-4-HYDROXY-2-OXO-QUINOLINE-3-CARBOXANILIDES AS AHR ACTIVATORS.

The present invention relates to compounds which are 1, 2-dihydro-4- hydroxy-2-oxo-quinoline-3-carboxanilides, their thieno-pyridone analogs, and prodrugs thereof. This invention specifically relates to such derivatives containing an N-hydrogen in the carboxanilide moiety and which exhibit modulating activity towards the aromatic hydrocarbon receptor (AhR), and, specifically, also to prodrugs thereof. The present invention also relates to use of said compounds as a medicament, and for the treatment of cancer, autoimmune disorders and other disorders with an immunological component, and a pharmaceutical composition comprising one or more of said compounds and a method of treatment.

METHOD FOR MANUFACTURING OF QUINOLINE-3-CARBOXAMIDES

A method for preparing a compound of formula (I) by reacting the appropriate alkyl ester and an aniline derivative, in a refluxing mixture containing an aliphatic solvent or a mixture of aliphatic solvents having a boiling point in the range of 68-191 °C; condensing vapors of the refluxing mixture; treating the condensed vapors with an alcohol scavenging agent or a mixture of alcohol scavenging agents; and returning the condensed vapors back to the reaction mixture.

NOVEL SOLID STATE FORMS OF LAQUINIMOD AND ITS SODIUM SALT

Provided herein is a novel crystalline form of laquinimod, process for the preparation, pharmaceutical compositions, and method of treating thereof. Provided also herein are novel amorphous and polymorphic forms of laquinimod sodium, process for the preparation, pharmaceutical compositions, and method of treating thereof.

2-OXO-1,2-DIHYDRO-QUINOLINE MODULATORS OF IMMUNE FUNCTION

The present invention relates to new 2-oxo-1,2-dihydro-quinoline modulators of immune function, pharmaceutical compositions thereof, and methods of use thereof.

NOVEL SOLID STATE FORMS OF LAQUINIMOD AND ITS SODIUM SALT

Provided herein is a novel crystalline form of laquinimod, process for the preparation, pharmaceutical compositions, and method of treating thereof. Provided also herein are novel amorphous and polymorphic forms of laquinimod sodium, process for the preparation, pharmaceutical compositions, and method of treating thereof.

HIGHLY PURE LAQUINIMOD OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF

Provided herein is an impurity of laquinimod, N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-1- methyl-2-oxoquinoline-3-carboxamide (deschloro laquinimod impurity), and process for preparation and isolation thereof. Provided further herein is a highly pure laquinimod or a pharmaceutically acceptable salt thereof substantially free of deschloro laquinimod impurity, processes for the preparation thereof, and pharmaceutical compositions comprising highly pure laquinimod or a pharmaceutically acceptable salt thereof substantially free of deschloro laquinimod impurity.